The long term objectives of this proposal are to provide a better understanding of the pathogenesis of HIV-1 during heterosexual transmission. Previous studies examining subjects early after infection, but primarily after HIV-1 seroconversion, have yielded valuable insights. For instance, we and other have shown that newly infected subjects only acquire a subset of viruses from the array of viral variants circulating in the transmitting partner. In addition, viruses with compact and less glycosylated variants are favored for heterosexual transmission. The biological mechanism for the selection of these envelope genotypes during heterosexual transmission remains undefined. The viral envelope glycoprotein structure would predict that short and less glycosylated envelopes would have more open conformations leading to an enhanced affinity for host cell receptors and possibly greater antibody neutralization sensitivity. Because envelope modifications can occur soon after infection in the setting of the host humoral immune response, we propose to evaluate and compare envelope properties from newly infected recipients sampled prior to HIV-1 seroconversion and their transmitting partner. We will investigate receptor interactions and cell infection efficiencies of the envelopes from recipients and donors. In addition, we will test whether greater efficiency in infecting host cells through better viral envelope glycoprotein-host cell receptor interactions could confer fitness for transmission. Our studies aim to examine potential biological mechanisms that provide an advantage for viruses during heterosexual transmission. Our studies could have significant implications for microbicides efforts aimed at using receptor and fusion inhibitors to prevent viral entry. PUBLIC HEALTH RELEVANCE: The aim of our proposal is to define the biological mechanisms that influence the selection of specific HIV-1 variants during transmission. We propose to examine a novel cohort of discordant couples to uniquely address receptor affinity and fusion kinetics differences among newly transmitted viruses and the majority of variants in the transmitting partner. We will explore the biological relevance of observed differences in these phenotypic properties to develop potential biological models for selection during HIV-1 transmission.